The high incidence of prostate cancer deaths in the USA is attributable to metastatic tumors present at initial diagnosis. In contrast to primary tumors that are often treated successfully by surgery and/or radiation, albeit with significant unwanted side effects, current therapies to treat metastatic prostate cancer, such as hormone ablation and chemotherapy, are ineffective. There is a clear need for a more effective therapy for these patients. Our long-term goal is to address this need by developing a gene therapy for metastatic prostate cancer that effectively manages the cancer, resulting in a longer, healthy life. Systemic delivery of targeted gene therapy holds great promise for improving the treatment of metastatic prostate cancer. Our objective is to introduce modifications to a promising new class of cationic, biodegradable, poly([unreadable]-amino ester) polymers that result in efficient, targeted nanoparticle-delivery of DNA to prostate tumor cells and associated neovasculature. Following synthesis and identification of modified polymers that deliver DNA payloads efficiently to cells in culture, we will use mouse models for prostate cancer to perform the ultimate test of their ability to deliver two suicide genes, a gene encoding diphtheria toxin and a fusion gene encoding cytosine deaminase + herpes simplex virus thymidine kinase to primary and metastatic prostate tumors. Our specific aims are to: 1. Generate single chain variable antibody fragments (scFvs) to two proteins on the surface of prostate tumor cells, a?[unreadable]3 integrin and prostate specific membrane antigen (PSMA). 2. Synthesize and screen modified poly([unreadable]-amino ester) polymers to identify nanoparticle formulations that deliver DNA efficiently to target cells in culture and are resistant to inactivation by serum. 3. Determine how effectively selected modifications poly([unreadable]-amino esters) (scFvs, tumor-targeting peptides, pegylation) or complexation of DNA/poly([unreadable]-amino ester)-nanoparticles with scFvs-poly(acrylic acid) target delivery of DNA to prostate tumor cells and reduce serum inhibition of DNA delivery following systemic administration to mice. 4. Determine how effectively targeted nanoparticle-delivery of suicide genes, administered systemically to mice, promotes regression of primary and metastatic prostate tumors, resulting in an increase in life span. While we focus here on the development of a new therapy for prostate cancer, accomplishing these specific aims will help establish the utility of nanoparticles for gene therapy and pave the way for their broader application for treating additional types of cancer and other diseases.